The teneurins are a family of four vertebrate type II transmembrane proteins preferentially expressed in the central nervous system (Baumgartner et al., 1994). The teneurins are about 2800 amino acids long and possess a short membrane spanning region. The extracellular face consists of a number of structurally distinct domains suggesting that the protein may possess a number of distinct functions (Minet and Chiquet-Ehrismann, 2000; Minet et al., 1999; Oohashi et al., 1999). The gene was originally discovered in Drosophila as a pair rule gene and was named tenascin-major (Ten-M) or Odz (Baumgartner et al., 1994; Levine et al., 1994). It is expressed in the Drosophila nervous system and targeted disruption of the genes leads to embryonic lethality (Baumgartner et al., 1994). In immortalized mouse cells, expression of the teneurin protein led to increased neurite outgrowth (Rubin et al., 1999).
The extracellular C-terminal region of each teneurin is characterized by a 40 or 41 amino acid sequence flanked by enzymatic cleavage sites, which predicts the presence of an amidated cleaved peptide (Qian et al., 2004; Wang et al., 2004). A synthetic version of this peptide was named teneurin C-terminus associated peptide (TCAP) and is active in vivo and in vitro. The mouse TCAP from teneurin-1 (TCAP-1) can modulate cAMP concentrations and proliferation in mouse hypothalamic cell lines as well as regulate the teneurin protein in a dose-dependent manner (Wang et al, 2004). Intracerebroventricular injection of TCAP-1 into rats can induce changes in the acoustic startle response three weeks after administration (Wang et al., 2004). [Also see, PCT/CA2003/000622, filed May 2, 2003, herein incorporated by reference; PCT/CA200300621, filed May 2, 2003, herein incorporated by reference; U.S. Ser. No. 11/706,376, filed Feb. 15, 2007, which claims the benefit and priority of provisional application No. 60/773,309, filed on Feb. 15, 2006, and provisional application No. 60/783,821, filed on Mar. 21, 2006, all of which are incorporated in their entirety by reference.]
Skeletal muscle is a critical regulator of glucose homeostasis. Skeletal muscle comprises the bulk of the body's insulin-sensitive tissue and is where insulin-induced glucose uptake is quantitatively most important (Wasserman et al., 2010; Abdul-Ghani and DeFronzo, 2010). Impairment in the response to insulin in skeletal muscle (i.e. an “insulin-resistant” state) leads to a marked reduction in glucose uptake (Brozimck et al., 1992; Wasserman et al., 2010; Abdul-Ghani and DeFronzo, 2010). Skeletal muscle insulin resistance is considered to be the initiating or primary defect for development of type 2 diabetes, sometimes evident years before failure of pancreatic β cells and onset of overt hyperglycemia (DeFronzo and Tripathy, 2009; Petersen et al., 2007; Wasserman et al., 2011).
Further, Type 1 diabetes is characterised by the absence of circulating insulin due to the autoimmune destruction of beta-cells in the pancreas. Patients are traditionally treated with multiple daily injections of exogenous insulin analogues. However, although these therapies improve quality of life, they are associated with the risk of hypoglycemic episodes and do not prevent the development of debilitating secondary complications. For these reasons, there is increasing demand for new therapies and preventions. Mann et al. (Curr Pharm Des. 2010; 16(8):1002-20-http://www.ncbi.nlm.nih.gov/pubmed/20041826) describe one approach, which is to the use of viral or non-viral gene therapy to modify skeletal muscle to produce and secrete insulin into the circulation and/or to increase muscle glucose uptake. Skeletal muscle is a desirable target tissue for the treatment of diabetes, including Type 1 diabetes) not only for its central role in whole body metabolism and glucose homeostasis, but also for its accessibility and amenability to many potential gene therapy technologies. However, gene therapy is quite complex, expensive and not optimal route.
Some glycogen storage diseases are also associated with improper glucose homeostasis in skeletal muscle cells. For example, glycogen storage disease type V (McArdle disease) results from a deficiency of the muscle isoform of the enzyme glycogen phosphorylase, which catalyzes glycogen to glucose for use in muscle (Robertshaw et al., 2007). In another example, glycogen storage disease type III is characterized by a deficiency in glycogen debranching enzymes which results in excess amounts of abnormal glycogen to be deposited in the liver and muscles (Preisler et al., 2013).
Skeletal muscle is also the primary site of glucose uptake during exercise (Wasserman et al., 2010; Richter and Hargreaves, 2013). Carbohydrate in the form of glucose becomes an increasingly important energy substrate with rising exercise intensity (Jensen and Richter, 2012; Holloszy and Kohrt, 1996). Blood glucose uptake into skeletal muscle cells can account for up to 40% of oxidative metabolism during exercise, and enhancing the availability of glucose delays muscle fatigue and increases performance (Richter and Hargreaves, 2013; Coyle et al., 1983).
In light of the above, there is a need to develop methods and compounds to stimulate glucose uptake by skeletal muscle cells and thereby increase the energy available to skeletal muscle cells in diseased and normal states.